The bio-availability of a drug to the therapeutic target is an important consideration in rational drug design. Before a drug elicits an effect, it has to pass through various cellular barriers either by passive diffusion and/or by carrier-mediated uptake. Depending on the location of the target site, the pH of the environment may vary considerably. Many molecules of biological interest contain acidic and/or basic groups which govern their biological properties. In particular, the ability of molecules to cross biological membranes is governed in part by the ionization state of the molecule in the pH of the surrounding medium. The proportion of neutral and charged molecular species present at a given pH is determined by the pKa value. The pKa can be determined by laborious and detailed measurements or by an empirical system of estimation developed over the years by Perrin et. al. With the advent of combinatorial synthesis and high throughput screening, the number of molecules for which it is desirable to know the pKa far exceeds the ability to synthesize the molecules and experimentally determine the pKa.